Closing-in Phenomenon in Huntington’s Disease: A Neuropsychological Marker of Frontal/Executive Dysfunction

Closing-in Phenomenon in Huntington’s Disease: A Neuropsychological Marker of Frontal/Executive... Abstract Objective In visuo-constructional tasks, patients may reproduce drawings near-to or superimposed on a model, showing the so-called “Closing-in” (CI), often ascribed to a defect in inhibitory control. CI has been described in neurological conditions, but no studies have explored CI in Huntington’s disease (HD), a neurodegenerative disorder often involving the frontal cortical–subcortical circuits. We searched for the occurrence of CI in HD patients and systematically investigated its correlates to find a clinical marker of the frontal/executive dysfunctions in the early examination of HD patients. Method We assessed 130 HD participants, who performed a graphic coping task and a neuropsychological, psychiatric, motor, and functional assessment. Results CI occurred in 52/130 (40%) HD patients, with 43/52 (82.7%) superimposing their copy directly on the model. MANOVA showed that HD patients with CI scored significantly poorer on Symbol digit modality test, Stroop-color word – reading test, Stroop-color word – interference test, Trail making test – part B, and Phonological verbal fluency test. However, a logistic regression analysis revealed that the significant predictor of the occurrence of CI was the score on Stroop-color word – interference test. Conclusions HD patients may show CI in graphic tasks, and it could be related to a defect in inhibitory control impeding the switch of attention from the model to the copying space, and releasing a default tendency which causes an attraction of hand movement towards the focus of visual attention. CI might be a useful clinical marker for the early detection of frontal/executive defects in HD patients. Drawing, Frontal defect, Huntington’s disease, Attention, Closing-in Introduction In graphic copying tasks, individuals may show a peculiar behavior labeled “Closing-in” (CI; Mayer Gross, 1935). This phenomenon consists of the tendency to reproduce a drawing in the space close to the model without coming in contact with it (near type of CI), or to directly superimpose the copying on the model (adherent type of CI). Both near- and adherent-CI have been commonly observed in normally developed children (Ambron, McIntosh, & Della Sala, 2010; Gainotti, 1972), and often reported in individuals with different kinds of dementia, including Alzheimer’s disease (De Lucia, Grossi, Fasanaro, Carpi, & Trojano, 2013; Grossi, De Lucia, & Trojano, 2015; Lee et al., 2004; Grossi, Orsini, & De Michele, 1978), cerebral vascular disease (De Lucia, Grossi, & Trojano, 2014; Kwak, 2004), fronto-temporal dementia (Grossi et al., 2015), and Parkinson’s disease with associated dementia (De Lucia, Grossi, Mauro, & Trojano, 2015; Poletti et al., 2012). Moreover, CI has been observed in individuals with neurodegenerative disorders without clinically relevant associated dementia (De Lucia et al., 2015b), and in focal brain-damaged patients (De Lucia, Grossi, & Trojano, 2016a; Gainotti, 1972). Such findings would suggest that CI might occur independently from the specific type of dementia. Indeed, it has been suggested that specific cognitive dysfunctions play a crucial role in the genesis of CI, regardless of clinical diagnosis. Early studies ascribed CI to impairments of visuo-spatial cognition, and described CI as a compensatory strategy to overcome visuo-perceptual or spatial memory dysfunctions (Lee et al., 2004; Serra, Fadda, Perri, Caltagirone, & Carlesimo, 2010). However, CI was not associated with poor scores on visuo-perceptual, visuo-spatial, or spatial memory tasks (De Lucia et al., 2014). Moreover, recent findings confirm that CI arises from frontal/executive dysfunctions (Ambron et al., 2010; De Lucia et al., 2013; Grossi et al., 2015). From this perspective, visuo-constructional copying tasks require the concurrent interactions of several mental procedures monitored by frontal/executive abilities. In particular, when asked to copy a figure, subjects have to perform a preliminary analysis of the stimulus, paying visual attention to the model, identifying in the figure the familiar elements already drawn in the past, and analyzing the spatial relationships between the elements of the model. These data are then processed, by means of procedural decisions requiring sustained and selective attention, to formulate a drawing plan including the specific strategies required to copy the model. This plan is preserved in a short-term memory buffer for as long as is necessary to translate it onto paper, by means of the activation of the motor programmes. After this executive stage, the frontal control processes perform a comparison between the reproduction and the original stimulus by switching visual attention from the model to the graphic copying in order to verify the accuracy of the copying process (Gasparini et al., 2008; Grossi & Trojano, 2001). Impairments of the frontal control functions impede the adequate inhibition of visual attention from the stimulus and move it onto the graphic reproduction and release a default tendency in which the manual performance migrates towards the focus of visual attention (De Ajuriaguerra et al., 1960; Gainotti, 1972; Kwon et al., 2002). The attraction of attention and action towards the model in graphic copying tasks has been recently confirmed in some studies which report that attraction towards the model was enhanced when participants are required to divide their attentional resources between two concurrent cognitive activities (De Lucia et al., 2014; McIntosh, Ambron, & Della Sala, 2008). Therefore, from this perspective one could expect to find occurrences of CI in neurodegenerative diseases with prevalent involvement of frontal/executive functions, independently from the occurrence of dementia. Among these disorders, Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG repeat in the gene encoding huntingtin (MacDonald et al., 1993), is most often characterized by impairments of frontal cortical–subcortical circuits with associated dysexecutive/frontal dysfunctions (Quarantelli et al., 2013; Stout, Paulsen, & Queller, 2011). However, CI has never been investigated in HD patients. In the present study, we aimed to explore the CI phenomenon in a large sample of HD patients by performing a qualitative and quantitative analysis of graphic performances, and to assessing whether CI is associated with frontal/executive abilities, other psychiatric or functional features, or disease-related motor defects. Methods Participants Among HD patients recruited in the Enroll-HD study of the European Huntington’s Disease Network (Euro-HD), we enrolled participants who met the following inclusion criteria: (i) positive molecular test for HD (CAG repeat length of greater than 38 repeats in the huntingtin gene); (ii) presence of clinically evident neurocognitive disease associated with HD, according to the DSM-IV diagnostic criteria (American Psychiatric Association, 1994); (iii) formal education of at least 2 years; and (iv) no other neurological disorders pathologically affecting cognitive function. One hundred and thirty HD patients (60 women and 70 men; education level range: 2–18 years) satisfied the inclusion criteria. We also enrolled a group of 30 healthy adults (18 females) of a similar age and education to HD sample, with no previous history of neurological or psychiatric diseases. All the participants gave their written informed consent to participate in the study, which was conducted in accordance with the Ethical Standards of Helsinki Declaration. Neuropsychological Assessment All the participants completed a neuropsychological, psychiatric, motor, and functional assessment scheduled in the Enroll-HD protocol. The neuropsychological assessment included the Italian version of the following tests: the Mini Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1975), providing a measure of general cognitive functioning; the Symbol digit modality test (Wechsler, 1981), requiring participants to make as many symbol–number associations as possible within 90 s, and providing a measure of information processing speed; the Category fluency task (Morris et al., 1989), requiring participants to reproduce in 1 min as many words as possible within the animal semantic category, and providing a measure of semantic knowledge; the Stroop-color word test (Treisman & Fearnley, 1969) consisting of three sections requiring the naming of colors (naming test), reading words (reading test), and the inhibition of the reading of color–words and the naming of the ink color in which each word is printed (interference test), and providing a measure of executive inhibition of irrelevant responses; the Trail making test (Kelland & Lewis, 1994), consisting of two parts in which participants have to draw lines to connect the numbers in ascending order (part A), and to draw lines to connect the circles by alternating between numbers and letters (i.e., 1-A-2-B-3-C; part B), and providing a measure of sustained and selective attention abilities; the Phonological verbal fluency (Benton & Hamsher, 1989), requiring patients to produce as many words beginning with the letter “F”, “P”, and “L” as they can in 1 min, and proving a measure of frontal mental flexibility. The psychiatric assessment consisted of the short version of the Problem Behaviors Assessment for HD (PBA; Craufurd, Thompson, & Snowden, 2001), an 11 item semi-structured clinical interview completed with patient and caregiver together, and evaluating depressed mood, suicidal ideation, anxiety, irritability, aggressive behavior, apathy, perseverative thinking, obsessive-compulsive behavior, delusion, hallucinations, and disoriented behavior. Each symptom was rated for severity and frequency independently on a 5-point (0–4) scale during the preceding 4-week period. A total PBA score for each symptom was then obtained by multiplying severity and frequency scores, with higher scores indicating more severe psychiatric disorder. Motor assessment was performed by means of the motor section of the Unified Huntington’s Disease Rating Scale (UHDSR; Huntington Study Group, HSG, 1996), a 15-item scale evaluating the motor signs of HD (i.e., oculo-motor function, dysarthria, finger tapping, chorea, dystonia, gait, postural stability, rigidity). Each symptom was rated on a 0–4 point scale; a total motor score was then obtained by adding together all the individual motor ratings, with higher scores indicating more severe motor impairment. Functional assessment was performed by means of the Total Functional Capacity (TFC) test included in the UHDRS (HSG, 1996), a 5-item scale evaluating functional capabilities (i.e., occupation, finances, routine domestic tasks, activities of daily living, and care level), with lower scores indicating more severe impairment of the functional status. Assessment of CI Presence and type of CI were detected by means of the pentagon copying task included in the MMSE (Folstein et al., 1975). Each participant was presented with an A4 stimulus sheet, with its long axis radially aligned in respect to the participant, showing a black-and-white drawing centrally printed in its upper half. The participant was explicitly required to reproduce the model in the lower half of the same sheet. For each graphic reproduction we recorded two types of CI: near-CI, when any point of the copy was produced within 10 mm of the lower side of the model; adherent-CI, when at least one element of the copy overlapped at least one element of the model. Then we computed the total number of CI and the number of near-CI and adherent-CI, in each patient. Data Analysis As a preliminary analysis, we computed descriptive statistics for presence of CI (near-CI or adherent-CI) based on the graphic reproduction in the pentagon copying of the MMSE for all participants. Then we performed two-tailed independent-sample t-tests to assess the differences on demographic data (age and education level), clinical data (CAG-repetition and disease duration), motor functions (UHDRS-motor), and functional abilities (TFC) between HD patients showing CI (including both near- and adherent-CI; CI group) and HD patients not showing CI (no-CI group). Moreover, we ran two separate multivariate analyses of variance (MANOVAs) to assess the differences on neuropsychological measures (MMSE, Symbol digit modality test, Category fluency, Stroop-color word test, Trail making test, and Phonological verbal fluency), and on psychiatric features (PBA), between HA group, CI group and no-CI group. Post-hoc analyses were performed by means of the Bonferroni-corrected post-hoc comparisons. Finally, in order to specifically find out which variables were associated with occurrence of CI in HD participants, we performed a forward logistic regression analysis. In particular, we considered as predictors the variables in which we detected significant differences between the no-CI and the CI groups, whereas the presence or not of CI (coding the absence of CI as 0, and the presence of CI as 1) was considered as the dependent variable. Results No healthy adults showed CI in the pentagon copying task (HA group). Among HD participants, 52 (40%) showed CI (CI group), in particular, nine (17.3%) produced near-CI, and 43 (82.7%) adherent-CI. The CI group did not differ from the no-CI group on demographic data, clinical data, motor functions or functional abilities (see Table 1). Table 1. Demographic and clinical data, motor functions, and functional abilities in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 Note: HA group (healthy adults); no-CI group (HD patients not showing Closing-in); CI group (HD patients showing Closing-in); UHDRS-motor (Unified Huntington Disease rating scale – motor score); TFC (total function capacity). Table 1. Demographic and clinical data, motor functions, and functional abilities in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 Note: HA group (healthy adults); no-CI group (HD patients not showing Closing-in); CI group (HD patients showing Closing-in); UHDRS-motor (Unified Huntington Disease rating scale – motor score); TFC (total function capacity). MANOVA on neuropsychological scores revealed a main effect of the group (Wilks’ lambda = .012; p < .001; ηp2 = .89). The HA group individuals achieved significantly higher scores on all the neuropsychological variables than the no-CI group and the CI group. Moreover, the CI group showed significantly lower scores than the no-CI group on the Symbol digit modality test, the Stroop-color word – reading test, the Stroop-color word – interference test, and on the Phonological verbal fluency test. Finally, the CI group was significantly slower on the Trail making test (part A, and part B) than the no-CI group. Conversely, no significant differences were found between these two groups on general cognitive functioning, the Stroop-color word – naming test, or category fluency (see Table 2). Table 2. Neuropsychological measures in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group; in bold the significant values between no-CI and CI group. Table 2. Neuropsychological measures in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group; in bold the significant values between no-CI and CI group. MANOVA on psychiatric features revealed a main effect of the group (Wilks’ lambda = .12; p = .02; ηp2 = .87). The HA participants scored differently from the no-CI and the CI group, whereas the no-CI group and the CI group achieved similar scores (see Table 3). Table 3. Psychiatric features in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group. Table 3. Psychiatric features in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group. Results from the logistic regression revealed that the model was statistically significant (Χ2 [8] = 7.625, p = .006; Cox & Snell R2 = .057). CI was only significantly associated with the scores on the Stroop-color word – interference test (Wald: 7.166, p = .007, odds ratio, OR: .955, 95% confidence interval, CI: .924–.988). Conversely, scores on the Symbol digit modality test (p = .14), Stroop-color word – reading test (p = .32), Phonological verbal fluency test (p = .32), and Trail making test (part A: p = .15; part B: .24) were not related to CI. Discussion Recently, findings have increasingly shown that patients suffering from frontal/executive dysfunctions may show CI in copying figures (De Lucia, Grossi, & Trojano, 2016b; Poletti et al., 2012). In the present study we investigated CI in a large sample of HD patients, a neurodegenerative disorder often associated with frontal/executive dysfunctions. By means of this assessment, we observed that 40% of our HD sample showed CI, thus highlighting that CI also occurs in HD individuals. We also assessed whether CI, in our HD patient sample, was associated with general cognitive functioning, frontal/executive abilities, psychiatric features, or disease-related motor defects. In our study the presence of CI was not associated with disease severity, nor genetic, psychiatric, functional, or motor defects, but rather only to a specific cognitive dysfunction, that is, impairments of frontal/executive cognition. Indeed, the CI group scored significantly lower than the no-CI group on tests assessing information processing speed, inhibition of irrelevant responses, sustained and selective attention, and mental flexibility abilities. These results suggested that the CI group showed greater difficulties in processing information to solve a problem, in paying attention to a specific focus for a long time and neglecting irrelevant stimuli, and in modifying cognitive strategies according to specific requests, compared to the no-CI group. In order to assess the individual contribution of each of these specific frontal impairments, we performed a logistic regression analysis and found out that the only significant variable associated with CI was the score on Stroop-color word – interference test. This outcome would suggest that performance on the test tapping susceptibility to cognitive interference could be the strongest significant and independent variable associated with CI in our patients. Therefore, in our HD patients the tendency to approach near, or directly onto, the model was associated with impairments in the inhibitory control system, which impede switching visual attention from the model to the copying space and release the attraction of hand movement towards the focus of visual attention (De Ajuriaguerra et al., 1960; Gainotti, 1972; Kwon et al., 2002). Interestingly, in our patient sample we also observed that most of our patients showing CI produced the adherent type of CI (82.7% adherent-CI vs. 17.3% near-CI). This pattern was consistent with previous findings reporting a higher percentage of adherent-CI in neurodegenerative diseases with more severe frontal/executive dysfunctions (De Lucia et al., 2013; Kwak, 2004), and it could confirm the hypothesis according to which different types of CI (near- and adherent-CI) could be ascribed to different severities of frontal/executive dysfunctions (De Lucia et al., 2013). However, an important limitation of the present study has to be taken into account. The neuropsychological assessment here performed was restricted to frontal/executive functions since the retrospective nature of the present study, and for this reason we could not investigate the possible associations between CI and performance in other cognitive domains. In conclusion, in the present study we observed that CI, and in particular the adherent type, is a recurrent behavior in HD patients, and that it might arise from a defect in the inhibition of visual attention to the model. This inhibition usually occurs in the process of shifting attention towards the copying space, thus the defect may result in default behavior, according to which the hand action migrates towards the focus of attention. Thus, CI might be a useful clinical marker for frontal/executive defects, and in particular for attention dysfunctions, helping clinicians with the early detection of these dysfunctions, although a more comprehensive neuropsychological assessment would be needed to better refine the cognitive mechanism underlying this phenomenon in HD patients. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement The authors would like to thank all patients and families for participation in the study, and the European Huntington’s Disease Network (Euro-HD) for the support. The authors thank Josh Williams for checking the English of this article. References Ambron , E. , McIntosh , R. D. , & Della Sala , S. ( 2010 ). Closing-in behaviour in preschool children . Cognitive Processing , 15 , 207 – 211 . doi:10.1007/s10339-009-0264-0 . Google Scholar CrossRef Search ADS American Psychiatric Association . 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Clinical Neuropsychology Oxford University Press

Closing-in Phenomenon in Huntington’s Disease: A Neuropsychological Marker of Frontal/Executive Dysfunction

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Abstract

Abstract Objective In visuo-constructional tasks, patients may reproduce drawings near-to or superimposed on a model, showing the so-called “Closing-in” (CI), often ascribed to a defect in inhibitory control. CI has been described in neurological conditions, but no studies have explored CI in Huntington’s disease (HD), a neurodegenerative disorder often involving the frontal cortical–subcortical circuits. We searched for the occurrence of CI in HD patients and systematically investigated its correlates to find a clinical marker of the frontal/executive dysfunctions in the early examination of HD patients. Method We assessed 130 HD participants, who performed a graphic coping task and a neuropsychological, psychiatric, motor, and functional assessment. Results CI occurred in 52/130 (40%) HD patients, with 43/52 (82.7%) superimposing their copy directly on the model. MANOVA showed that HD patients with CI scored significantly poorer on Symbol digit modality test, Stroop-color word – reading test, Stroop-color word – interference test, Trail making test – part B, and Phonological verbal fluency test. However, a logistic regression analysis revealed that the significant predictor of the occurrence of CI was the score on Stroop-color word – interference test. Conclusions HD patients may show CI in graphic tasks, and it could be related to a defect in inhibitory control impeding the switch of attention from the model to the copying space, and releasing a default tendency which causes an attraction of hand movement towards the focus of visual attention. CI might be a useful clinical marker for the early detection of frontal/executive defects in HD patients. Drawing, Frontal defect, Huntington’s disease, Attention, Closing-in Introduction In graphic copying tasks, individuals may show a peculiar behavior labeled “Closing-in” (CI; Mayer Gross, 1935). This phenomenon consists of the tendency to reproduce a drawing in the space close to the model without coming in contact with it (near type of CI), or to directly superimpose the copying on the model (adherent type of CI). Both near- and adherent-CI have been commonly observed in normally developed children (Ambron, McIntosh, & Della Sala, 2010; Gainotti, 1972), and often reported in individuals with different kinds of dementia, including Alzheimer’s disease (De Lucia, Grossi, Fasanaro, Carpi, & Trojano, 2013; Grossi, De Lucia, & Trojano, 2015; Lee et al., 2004; Grossi, Orsini, & De Michele, 1978), cerebral vascular disease (De Lucia, Grossi, & Trojano, 2014; Kwak, 2004), fronto-temporal dementia (Grossi et al., 2015), and Parkinson’s disease with associated dementia (De Lucia, Grossi, Mauro, & Trojano, 2015; Poletti et al., 2012). Moreover, CI has been observed in individuals with neurodegenerative disorders without clinically relevant associated dementia (De Lucia et al., 2015b), and in focal brain-damaged patients (De Lucia, Grossi, & Trojano, 2016a; Gainotti, 1972). Such findings would suggest that CI might occur independently from the specific type of dementia. Indeed, it has been suggested that specific cognitive dysfunctions play a crucial role in the genesis of CI, regardless of clinical diagnosis. Early studies ascribed CI to impairments of visuo-spatial cognition, and described CI as a compensatory strategy to overcome visuo-perceptual or spatial memory dysfunctions (Lee et al., 2004; Serra, Fadda, Perri, Caltagirone, & Carlesimo, 2010). However, CI was not associated with poor scores on visuo-perceptual, visuo-spatial, or spatial memory tasks (De Lucia et al., 2014). Moreover, recent findings confirm that CI arises from frontal/executive dysfunctions (Ambron et al., 2010; De Lucia et al., 2013; Grossi et al., 2015). From this perspective, visuo-constructional copying tasks require the concurrent interactions of several mental procedures monitored by frontal/executive abilities. In particular, when asked to copy a figure, subjects have to perform a preliminary analysis of the stimulus, paying visual attention to the model, identifying in the figure the familiar elements already drawn in the past, and analyzing the spatial relationships between the elements of the model. These data are then processed, by means of procedural decisions requiring sustained and selective attention, to formulate a drawing plan including the specific strategies required to copy the model. This plan is preserved in a short-term memory buffer for as long as is necessary to translate it onto paper, by means of the activation of the motor programmes. After this executive stage, the frontal control processes perform a comparison between the reproduction and the original stimulus by switching visual attention from the model to the graphic copying in order to verify the accuracy of the copying process (Gasparini et al., 2008; Grossi & Trojano, 2001). Impairments of the frontal control functions impede the adequate inhibition of visual attention from the stimulus and move it onto the graphic reproduction and release a default tendency in which the manual performance migrates towards the focus of visual attention (De Ajuriaguerra et al., 1960; Gainotti, 1972; Kwon et al., 2002). The attraction of attention and action towards the model in graphic copying tasks has been recently confirmed in some studies which report that attraction towards the model was enhanced when participants are required to divide their attentional resources between two concurrent cognitive activities (De Lucia et al., 2014; McIntosh, Ambron, & Della Sala, 2008). Therefore, from this perspective one could expect to find occurrences of CI in neurodegenerative diseases with prevalent involvement of frontal/executive functions, independently from the occurrence of dementia. Among these disorders, Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG repeat in the gene encoding huntingtin (MacDonald et al., 1993), is most often characterized by impairments of frontal cortical–subcortical circuits with associated dysexecutive/frontal dysfunctions (Quarantelli et al., 2013; Stout, Paulsen, & Queller, 2011). However, CI has never been investigated in HD patients. In the present study, we aimed to explore the CI phenomenon in a large sample of HD patients by performing a qualitative and quantitative analysis of graphic performances, and to assessing whether CI is associated with frontal/executive abilities, other psychiatric or functional features, or disease-related motor defects. Methods Participants Among HD patients recruited in the Enroll-HD study of the European Huntington’s Disease Network (Euro-HD), we enrolled participants who met the following inclusion criteria: (i) positive molecular test for HD (CAG repeat length of greater than 38 repeats in the huntingtin gene); (ii) presence of clinically evident neurocognitive disease associated with HD, according to the DSM-IV diagnostic criteria (American Psychiatric Association, 1994); (iii) formal education of at least 2 years; and (iv) no other neurological disorders pathologically affecting cognitive function. One hundred and thirty HD patients (60 women and 70 men; education level range: 2–18 years) satisfied the inclusion criteria. We also enrolled a group of 30 healthy adults (18 females) of a similar age and education to HD sample, with no previous history of neurological or psychiatric diseases. All the participants gave their written informed consent to participate in the study, which was conducted in accordance with the Ethical Standards of Helsinki Declaration. Neuropsychological Assessment All the participants completed a neuropsychological, psychiatric, motor, and functional assessment scheduled in the Enroll-HD protocol. The neuropsychological assessment included the Italian version of the following tests: the Mini Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1975), providing a measure of general cognitive functioning; the Symbol digit modality test (Wechsler, 1981), requiring participants to make as many symbol–number associations as possible within 90 s, and providing a measure of information processing speed; the Category fluency task (Morris et al., 1989), requiring participants to reproduce in 1 min as many words as possible within the animal semantic category, and providing a measure of semantic knowledge; the Stroop-color word test (Treisman & Fearnley, 1969) consisting of three sections requiring the naming of colors (naming test), reading words (reading test), and the inhibition of the reading of color–words and the naming of the ink color in which each word is printed (interference test), and providing a measure of executive inhibition of irrelevant responses; the Trail making test (Kelland & Lewis, 1994), consisting of two parts in which participants have to draw lines to connect the numbers in ascending order (part A), and to draw lines to connect the circles by alternating between numbers and letters (i.e., 1-A-2-B-3-C; part B), and providing a measure of sustained and selective attention abilities; the Phonological verbal fluency (Benton & Hamsher, 1989), requiring patients to produce as many words beginning with the letter “F”, “P”, and “L” as they can in 1 min, and proving a measure of frontal mental flexibility. The psychiatric assessment consisted of the short version of the Problem Behaviors Assessment for HD (PBA; Craufurd, Thompson, & Snowden, 2001), an 11 item semi-structured clinical interview completed with patient and caregiver together, and evaluating depressed mood, suicidal ideation, anxiety, irritability, aggressive behavior, apathy, perseverative thinking, obsessive-compulsive behavior, delusion, hallucinations, and disoriented behavior. Each symptom was rated for severity and frequency independently on a 5-point (0–4) scale during the preceding 4-week period. A total PBA score for each symptom was then obtained by multiplying severity and frequency scores, with higher scores indicating more severe psychiatric disorder. Motor assessment was performed by means of the motor section of the Unified Huntington’s Disease Rating Scale (UHDSR; Huntington Study Group, HSG, 1996), a 15-item scale evaluating the motor signs of HD (i.e., oculo-motor function, dysarthria, finger tapping, chorea, dystonia, gait, postural stability, rigidity). Each symptom was rated on a 0–4 point scale; a total motor score was then obtained by adding together all the individual motor ratings, with higher scores indicating more severe motor impairment. Functional assessment was performed by means of the Total Functional Capacity (TFC) test included in the UHDRS (HSG, 1996), a 5-item scale evaluating functional capabilities (i.e., occupation, finances, routine domestic tasks, activities of daily living, and care level), with lower scores indicating more severe impairment of the functional status. Assessment of CI Presence and type of CI were detected by means of the pentagon copying task included in the MMSE (Folstein et al., 1975). Each participant was presented with an A4 stimulus sheet, with its long axis radially aligned in respect to the participant, showing a black-and-white drawing centrally printed in its upper half. The participant was explicitly required to reproduce the model in the lower half of the same sheet. For each graphic reproduction we recorded two types of CI: near-CI, when any point of the copy was produced within 10 mm of the lower side of the model; adherent-CI, when at least one element of the copy overlapped at least one element of the model. Then we computed the total number of CI and the number of near-CI and adherent-CI, in each patient. Data Analysis As a preliminary analysis, we computed descriptive statistics for presence of CI (near-CI or adherent-CI) based on the graphic reproduction in the pentagon copying of the MMSE for all participants. Then we performed two-tailed independent-sample t-tests to assess the differences on demographic data (age and education level), clinical data (CAG-repetition and disease duration), motor functions (UHDRS-motor), and functional abilities (TFC) between HD patients showing CI (including both near- and adherent-CI; CI group) and HD patients not showing CI (no-CI group). Moreover, we ran two separate multivariate analyses of variance (MANOVAs) to assess the differences on neuropsychological measures (MMSE, Symbol digit modality test, Category fluency, Stroop-color word test, Trail making test, and Phonological verbal fluency), and on psychiatric features (PBA), between HA group, CI group and no-CI group. Post-hoc analyses were performed by means of the Bonferroni-corrected post-hoc comparisons. Finally, in order to specifically find out which variables were associated with occurrence of CI in HD participants, we performed a forward logistic regression analysis. In particular, we considered as predictors the variables in which we detected significant differences between the no-CI and the CI groups, whereas the presence or not of CI (coding the absence of CI as 0, and the presence of CI as 1) was considered as the dependent variable. Results No healthy adults showed CI in the pentagon copying task (HA group). Among HD participants, 52 (40%) showed CI (CI group), in particular, nine (17.3%) produced near-CI, and 43 (82.7%) adherent-CI. The CI group did not differ from the no-CI group on demographic data, clinical data, motor functions or functional abilities (see Table 1). Table 1. Demographic and clinical data, motor functions, and functional abilities in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 Note: HA group (healthy adults); no-CI group (HD patients not showing Closing-in); CI group (HD patients showing Closing-in); UHDRS-motor (Unified Huntington Disease rating scale – motor score); TFC (total function capacity). Table 1. Demographic and clinical data, motor functions, and functional abilities in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD Demographic data  Age (years) — 50.62 9.44 49.54 12.47 51.10 12.47  Education (years) — 9.87 3.73 9.39 3.67 9.19 3.54 Clinical data  CAG repeats — — — 45.02 3.51 44.92 3.66  Disease duration — — — 4.06 2.51 4.48 2.30 Motor functions  UHDRS-motor 0–124 — — 32.96 24.78 33.00 26.46 Functional abilities  TFC 0–13 — — 6.92 4.64 7.11 4.52 Note: HA group (healthy adults); no-CI group (HD patients not showing Closing-in); CI group (HD patients showing Closing-in); UHDRS-motor (Unified Huntington Disease rating scale – motor score); TFC (total function capacity). MANOVA on neuropsychological scores revealed a main effect of the group (Wilks’ lambda = .012; p < .001; ηp2 = .89). The HA group individuals achieved significantly higher scores on all the neuropsychological variables than the no-CI group and the CI group. Moreover, the CI group showed significantly lower scores than the no-CI group on the Symbol digit modality test, the Stroop-color word – reading test, the Stroop-color word – interference test, and on the Phonological verbal fluency test. Finally, the CI group was significantly slower on the Trail making test (part A, and part B) than the no-CI group. Conversely, no significant differences were found between these two groups on general cognitive functioning, the Stroop-color word – naming test, or category fluency (see Table 2). Table 2. Neuropsychological measures in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group; in bold the significant values between no-CI and CI group. Table 2. Neuropsychological measures in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Neuropsychological measures  Mini Mental State Examination 0–30 29.10 3.23 22.94* 4.80 21.59* 5.10 .13 .01  Symbol digit modality test — 34.52 8.27 18.69* 11.53 13.73* 11.07 .01 .04  Category fluency — 22.01 4.28 10.87* 5.49 8.99* 6.04 .07 .02  Stroop-color word – naming test — 66.57 9.26 35.73* 18.64 30.81* 18.64 .14 .01  Stroop-color word – reading test — 72.21 9.37 52.42* 26.76 42.21* 23.58 .02 .03  Stroop-color word – interference test — 29.81 8.81 20.60* 11.43 15.15* 10.36 .006 .05  Trail making test (part A) – time (sec) 0–240 46.22 22.10 79.94* 39.32 97.47* 43.98 .02 .04  Trail making test (part A) – correct responses 0–25 24.98 3.83 24.88* 9.32 24.51* 9.67 .82 <.001  Trail making test (part B) – time (sec) 0–240 68.90 24.49 194.56* 66.41 215.42* 49.37 .04 .03  Trail making test (part B) – correct responses 0–25 22.90 6.45 14.73* 8.01 12.22* 7.43 .07 .02  Phonological verbal fluency — 32.33 5.65 15.25* 12.77 11.18* 8.79 .03 .03 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group; in bold the significant values between no-CI and CI group. MANOVA on psychiatric features revealed a main effect of the group (Wilks’ lambda = .12; p = .02; ηp2 = .87). The HA participants scored differently from the no-CI and the CI group, whereas the no-CI group and the CI group achieved similar scores (see Table 3). Table 3. Psychiatric features in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group. Table 3. Psychiatric features in HD patients and healthy adults HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 HA group (n = 30) no-CI group (n = 78) CI group (n = 52) Score range Mean SD Mean SD Mean SD p ηp2 Psychiatric features  Depressed mood 0–16 1.22 2.01 3.38* 4.07 3.79* 4.32 .58 .002  Suicidal ideation 0–16 0.11 1.01 0.51* 1.36 0.94* 2.56 .27 .009  Anxiety 0–16 1.19 1.56 3.50* 4.24 2.76* 3.73 .29 .009  Irritability 0–16 0.34 0.28 2.73* 4.09 3.12* 4.60 .61 .002  Aggressive behavior 0–16 0.10 0.32 2.00* 3.36 2.30* 4.69 .68 .001  Apathy 0–16 2.02 1.38 3.55* 4.96 3.55* 4.60 .99 .001  Perseverative thinking 0–16 0.68 0.27 2.09* 3.34 2.47* 4.34 .59 .002  Obsessive-compulsive behavior 0–16 1.16 1.04 2.76* 4.95 1.92* 3.90 .28 .009  Delusion 0–16 0.13 1.27 0.92* 2.50 0.39* 1.55 .14 .01  Hallucination 0–16 0.17 1.46 0.32* 1.74 0.24* 1.81 .79 .001  Disoriented behavior 0–16 0.37 1.48 1.67* 2.79 1.37* 2.46 .51 .003 Note: HA group (healthy adults); no-CI group (patients not showing Closing-in); CI group (patients showing Closing-in); *significant different from HA group. Results from the logistic regression revealed that the model was statistically significant (Χ2 [8] = 7.625, p = .006; Cox & Snell R2 = .057). CI was only significantly associated with the scores on the Stroop-color word – interference test (Wald: 7.166, p = .007, odds ratio, OR: .955, 95% confidence interval, CI: .924–.988). Conversely, scores on the Symbol digit modality test (p = .14), Stroop-color word – reading test (p = .32), Phonological verbal fluency test (p = .32), and Trail making test (part A: p = .15; part B: .24) were not related to CI. Discussion Recently, findings have increasingly shown that patients suffering from frontal/executive dysfunctions may show CI in copying figures (De Lucia, Grossi, & Trojano, 2016b; Poletti et al., 2012). In the present study we investigated CI in a large sample of HD patients, a neurodegenerative disorder often associated with frontal/executive dysfunctions. By means of this assessment, we observed that 40% of our HD sample showed CI, thus highlighting that CI also occurs in HD individuals. We also assessed whether CI, in our HD patient sample, was associated with general cognitive functioning, frontal/executive abilities, psychiatric features, or disease-related motor defects. In our study the presence of CI was not associated with disease severity, nor genetic, psychiatric, functional, or motor defects, but rather only to a specific cognitive dysfunction, that is, impairments of frontal/executive cognition. Indeed, the CI group scored significantly lower than the no-CI group on tests assessing information processing speed, inhibition of irrelevant responses, sustained and selective attention, and mental flexibility abilities. These results suggested that the CI group showed greater difficulties in processing information to solve a problem, in paying attention to a specific focus for a long time and neglecting irrelevant stimuli, and in modifying cognitive strategies according to specific requests, compared to the no-CI group. In order to assess the individual contribution of each of these specific frontal impairments, we performed a logistic regression analysis and found out that the only significant variable associated with CI was the score on Stroop-color word – interference test. This outcome would suggest that performance on the test tapping susceptibility to cognitive interference could be the strongest significant and independent variable associated with CI in our patients. Therefore, in our HD patients the tendency to approach near, or directly onto, the model was associated with impairments in the inhibitory control system, which impede switching visual attention from the model to the copying space and release the attraction of hand movement towards the focus of visual attention (De Ajuriaguerra et al., 1960; Gainotti, 1972; Kwon et al., 2002). Interestingly, in our patient sample we also observed that most of our patients showing CI produced the adherent type of CI (82.7% adherent-CI vs. 17.3% near-CI). This pattern was consistent with previous findings reporting a higher percentage of adherent-CI in neurodegenerative diseases with more severe frontal/executive dysfunctions (De Lucia et al., 2013; Kwak, 2004), and it could confirm the hypothesis according to which different types of CI (near- and adherent-CI) could be ascribed to different severities of frontal/executive dysfunctions (De Lucia et al., 2013). However, an important limitation of the present study has to be taken into account. The neuropsychological assessment here performed was restricted to frontal/executive functions since the retrospective nature of the present study, and for this reason we could not investigate the possible associations between CI and performance in other cognitive domains. In conclusion, in the present study we observed that CI, and in particular the adherent type, is a recurrent behavior in HD patients, and that it might arise from a defect in the inhibition of visual attention to the model. This inhibition usually occurs in the process of shifting attention towards the copying space, thus the defect may result in default behavior, according to which the hand action migrates towards the focus of attention. Thus, CI might be a useful clinical marker for frontal/executive defects, and in particular for attention dysfunctions, helping clinicians with the early detection of these dysfunctions, although a more comprehensive neuropsychological assessment would be needed to better refine the cognitive mechanism underlying this phenomenon in HD patients. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement The authors would like to thank all patients and families for participation in the study, and the European Huntington’s Disease Network (Euro-HD) for the support. The authors thank Josh Williams for checking the English of this article. References Ambron , E. , McIntosh , R. D. , & Della Sala , S. ( 2010 ). Closing-in behaviour in preschool children . Cognitive Processing , 15 , 207 – 211 . doi:10.1007/s10339-009-0264-0 . Google Scholar CrossRef Search ADS American Psychiatric Association . 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Archives of Clinical NeuropsychologyOxford University Press

Published: Mar 15, 2018

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